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Original Article Singapore Med J 2009; 50(12) : 1177 Association between left ventricular hypertrophy with retinopathy and renal dysfunction in patients with essential hypertension Shirafkan A, Motahari M, Mojerlou M, Rezghi Z, Behnampour N, Gholamrezanezhad A ABSTRACT Introduction Introduction : It has been suggested that Hypertension (HTN) is the most common cardiovascular hypertension (HTN) is associated with certain target organ damage (TOD) and related clinical conditions. On the other hand, left ventricular Golestan Heart Research Center and Department of Cardiology, 5th Azar Hospital, Golestan University of Medical Sciences, 5th Azar Avenue, Gorgan, Iran Shirafkan A, MD Assistant Professor Department of Ophthalmology hypertrophy (LVH) has been considered as an independent risk factor of cardiovascular events and death. The aim of this study was to examine the relationship between HTN-induced LVH and TOD (retinopathy and renal failure). Methods: We assessed 102 hypertensive subjects (43 males and 59 females) with a mean age of 60.2 +/− 8.8 (range 35–81) years. LVH was defined as a left ventricular mass index (LVMI) of more than Motahari M, MD Assistant Professor 51 and 47 g/(m [to the power of 2.7]), in men and Department of Nephrology on ophthalmological examination was defined Mojerlou M, MD Assistant Professor Serum creatinine, blood urea nitrogen and urine Department of Public Health women, respectively. The degree of retinopathy according to the Keith-Wagener classification. protein concentrations were also measured. Rezghi Z, MD Registrar Results: Hypertensive retinopathy was found in Department of Biostatistics, Faculty of Health 28.5 percent; III 3.9 percent; IV: 3.9 percent). The Behnampour N, MSc Statistical Associate Golestan Heart Research Center and Research Institute for Nuclear Medicine, Shariati Hospital, Tehran University of Medical Sciences, North Karegar Street, Tehran 14114, Iran Gholamrezanezhad A, MD, FEBNM Research Officer 94 (92.2 percent) cases (Grades I 55.9 percent; II mean systolic and diastolic blood pressures and serum creatinine concentration showed significant correlation with the severity of LVH. There was no significant relationship between LVH severity and retinopathy or proteinuria. Conclusion: The tight control of systolic and diastolic blood pressures in the first step of essential hypertension can assist to postpone LVH. Furthermore, routine measurement of serum disease.(1) The disease which was considered to be rare outside of Europe and America in the early 1900s, is now diagnosed in more than 25% of the population throughout the world.(1,2) Although HTN is often asymptomatic, the disease is related to different types of target organ damage (TOD) and associated clinical conditions. (2) Subtle TOD, such as left ventricular (LV) hypertrophy (LVH), retinopathy, microalbuminuria and cognitive dysfunction, occurs early in the course of hypertensive disease, while catastrophic events, such as stroke, heart attack, renal failure and dementia, are usually a result of a long period of uncontrolled HTN complications.(3,4) On the other hand, echocardiographically-determined LV mass (LVM) indices, corrected for either body surface area or patients’ height, are independent risk predictors of cardiovascular disease and chronic heart failure.(5-9) Hence, these indices as well as other factors, such as the severity of retinopathy and renal dysfunction (all evidences of TOD), were confirmed to be major predictors of cardiovascular mortality and morbidity among hypertensive patients.(10-12) In selected populations such as those with HTN, renal dysfunction was found to be related to LVH.(11) Some authors also claimed that LVH is an independent predictor for extracardiac TODs in essential HTN.(13) In fact, some of the previous reports revealed that there is a significant association between different types of TOD in hypertensive populations.(14-16) Unfortunately, discordant conclusions on this matter emphasise the need for further investigation on such relationships.(17,18) Therefore, the aim of this study was to examine the relationship between LVH and other signs of TODs (retinopathy and renal failure) secondary to systemic HTN. creatinine can predict the risk of cardiovascular Methods complications in the hypertensive patient. The study was carried out from January to September Correspondence to: Dr Ali Gholamrezanezhad Keywords: essential hypertension, left ventricular Tel: (98) 912 210 7037 Fax: (98) 212 284 6272 hypertrophy, renal dysfunction, retinopathy Email: gholamrezanej Singapore Med J 2009; 50(12): 1177-1183 [email protected] 2006 in the heart clinic of our university hospital. 102 consecutive patients (mean age 60.2 ± 8.8 years; range 35– 81 years) with the diagnosis of HTN-induced LVH (based on electrocardiography [ECG] and echocardiography Singapore Med J 2009; 50(12) : 1178 Table I. Prevalence of left ventricular hypertrophy on electrocardiography in different classes of left ventricular hypertrophy on echocardiography. Severity of LVH on echocardiography No. (%) of patients with LVH on ECG Mild Moderate Severe Total No. (%) of patients without LVH on ECG 12 (20.3) 13 (36.1) 4 (57.1) 29 (28.4) 47 (79.7) 23 (63.9) 3 (42.9) 73 (71.6) Total 59 36 7 102 LVH: left ventricular hypertrophy; ECG: electrocardiography findings and ruling out other possible aetiologies of LVH) depression or T-wave inversion in leads V5–V6).(23,24) were evaluated. All the patients were newly diagnosed and untreated. Cases with the following conditions were referred to an ophthalmologist for the retinal examination. excluded from the study: echocardiographic features Based on the Keith-Wagener classification,(25) the or positive family history indicative of hypertrophic retinopathy was categorised into four grades. Serum cardiomyopathy; and the presence of any other known creatinine and blood urea nitrogen (BUN) were measured disease, which was completely or partially responsible for for all the patients, according to the routine laboratory renal dysfunction or retinal abnormality (such as diabetes policy. Data was expressed as means ± standard deviation mellitus and genetic or autoimmune diseases affecting (SD). The analysis of variance test was used to assess the retinal or renal integration). relationship between the different variables and the three All the patients, whose records were blinded, were The blood pressure (BP) was measured with an arm- groups of LVH severity. Statistical analysis was performed cuff and a mercury sphygmomanometer after the patient via the Statistical Package for Social Sciences version 11.5 had been resting in a sitting position for five minutes. (SPSS Inc, Chicago, IL, USA). Systolic and diastolic BP measurements were taken as the first and fifth phase of the Korotkoff sounds, respectively. Results HTN was defined as a systolic BP ≥ 140 mmHg and/or Out of 102 patients, 43 (42.2%) were male and 59 diastolic BP ≥ 90 mmHg on two measurements taken with (57.8%) were female. Based on the LVH classification on a one-day interval. echocardiographical evaluation, 59, 36 and seven patients M-mode, two-dimensional echocardiographic had mild, moderate and severe LVH, respectively. Out examinations were performed for all the subjects in the of the 102 patients with LVH on echocardiography, partial left decubitus position, using a Esaote Caris Plus only 29 (28.4%) showed characteristic features of machine (Caris Plus, Esaote SpA, Genoa, Italy) and a LVH on ECG (Table I). The relationship between 2.5–3.5 MHz electrical transducer (Carius Plus, Esaote echocardiographically-diagnosed and ECG-detected SpA, Genoa, Italy). End-diastolic left ventricular internal LVH was statistically significant (p < 0.01). There were diameter (LVIDd), septal wall thickness (SWT) and significant associations between the severity of LVH on posterior wall thickness (PWT) were calculated from the echocardiography and the mean systolic and diastolic two-dimensionally-guided M-mode tracings and measured BPs (both p-values < 0.01) (Table II). There was also a in five consecutive cardiac cycles, according to the Penn significant correlation between the severity of LVH and Convention.(19) the patients’ age (p-values < 0.01) (Table III). LVM was determined by Devereux’s formula: LVM Only eight patients (7.8%) showed a normal retinal = 1.04 × {[(LVIDd + PWT + SWT)3 − LVIDd3] − 13.6}. examination, while 55.9%, 28.4%, 3.9% and 3.9% Subsequently LVM was divided by height2.7 in order to of the patients respectively revealed Grades 1, 2, 3 2.7 (20) evaluate the LVM index (LVMI) in terms of g/m . and 4 retinopathy. As shown in Table IV, there was no LVH was respectively defined as LVMI > 51 g/m2.7 in men statistically-significant relationship between the grade and > 47 g/m On the basis of the SWT, of LVH and the severity of retinal hypertensive disease LVH was stratified into no LVH (6 < SWT ≤ 11 mm), mild (p > 0.05). As shown in Table V, by increasing the LVH (11 < SWT 15 ≤ mm), moderate (15 < SWT ≤ 18 mm), grading on echocardiography, the serum creatinine and severe LVH (SWT > 18 mm).(22) For detecting LVH, and BUN also increased, and this was statistically two different ECG criteria were used: the Sokolow-Lyon significant (p = 0.001). Although 23 patients showed voltage (sum of amplitude of S-wave in V1 and R-wave elevated urine protein levels, there was no significant in V5 or V6 > 35 mm) and LV strain pattern (ST-segment statistical relationship between the severity of LVH on 2.7 in women. (17,21) Singapore Med J 2009; 50(12) : 1179 Table II. Association between systolic and diastolic blood pressures and severity of left ventricular hypertrophy on echocardiography. Severity of LVH No. of on echocardiography patients Mean ± SD systolic BP (mmHg) Mean ± SD diastolic BP (mmHg) Mild Moderate Severe Total 147.4 ± 18.4 159.3 ± 23.8 157.1 ± 25.0 152.3 ± 21.5 87.2 ± 10.1 90.5 ± 11.8 88.5 ± 10.7 88.5 ± 10.8 59 36 7 102 LVH: left ventricular hypertrophy; SD: standard deviation; BP: blood pressure Table III. Association between patients’ age and severity of left ventricular hypertrophy on echocardiography. Severity of LVH No. of patients on echocardiography Mean ± SD age (year) Mild Moderate Severe Total 58.7 ± 8.3 61.1 ± 9.2 67.0 ± 8.2 60.1 ± 8.8 59 36 7 102 LVH: left ventricular hypertrophy; SD: standard deviation that if the BP was well-controlled, a normal LVM would be expected. Their findings also seemed to suggest that echocardiography and the severity of proteinuria (p > the association of BP with LVM in hypertensive patients 0.05). may partially explain the increased cardiovascular risk. However, in a few investigations, there was no significant Discussion correlation between the LVMI and diastolic BP, or even The present study showed a positive correlation between the systolic BP.(42-44) Some investigators concluded that LVH and age. This important correlation can be due diastolic BP was not a reliable parameter in association to a long duration of undiagnosed HTN (even though to LVH,(43,44) and others suggested that although the office all the patients were newly diagnosed). This possible or home BP did not have a remarkable correlation with explanation of the study findings should be kept in the LVM, the 24-hour ambulatory BP had a stronger mind in future investigations. LVH is one of the most correlation to the LV structural indices.(45) serious complications of HTN, and it has been strongly associated with an increased incidence of heart failure, although weak association between the 24-hour BP and coronary artery disease, myocardial infarction, cardiac LVM in hypertensive patients.(17,46) These researchers arrhythmias and sudden death. On the other hand, some studies revealed a definite, Based on these facts, were convinced that systolic BP, mean heart rate and its early detection is mandatory in order to obtain LVH standard deviation over 24 hours contributed to LVM in regression, using certain adequate antihypertensive hypertensive subjects. Schillaci et al asserted that even in drugs.(27,28) patients with well-controlled HTN, the LVM was greater Conventional ECG has been thought to be a less than that of normotensive individuals who were matched accurate method than echocardiography for detecting by confounding factors (such as the patient’s age, gender, well-established LVH.(29) It is striking that even the obesity, and clinic and 24-hour BPs). This finding is more accurate method using echocardiography failed compatible with the fact that during antihypertensive to detect 70%–80% of patients suffering from LVH in therapy, a reduction in the coronary heart disease risk non-selected hypertensive patients and also in those with is lower than expected, and that in treated patients with mild to moderate HTN.(29,30) Hence, previous reports essential HTN, some factors (haemodynamic and/or non- have emphasised that relying on ECG to diagnose LVH haemodynamic) other than BP may affect the LVM.(47) in hypertensive patients, with its satisfactory specificity The results from the current research were consistent with but low sensitivity, is not logical.(18,29-32) Based on our the majority of the previous studies that showed positive study findings (Table I), the more severe the LVH is on associations between the systolic and diastolic BPs echocardiography, the more likely it would be diagnosed and LVMI in hypertensive patients. Our investigation on ECG. Hence, ECG is not a reliable method for confirmed that the more severe and uncontrolled screening hypertensive patients for LVH, particularly in the BP, the more severe the LVH. Additionally, the mild to moderate cases. older the patient, the more severe the LVH was on echocardiographical analysis. (7,26) The existing correlation between the LVMI and systolic and diastolic BPs, as well as the mean arterial pressure, had been previously evaluated by other authors were affected by retinopathy,(17) compared to 92.1% of via 24-hour ambulatory BP monitoring (ABPM) or home patients in our study. This difference between the two BP monitoring, and compared with LVMI. These studies was most likely because our subjects were those studies found a significant correlation of LVMI with who had LVH. This evidence could be indirectly indicative systolic and diastolic BPs, and most of them concluded of an increased prevalence of retinopathy in hypertensive (14,33-42) In Palatini et al’s study, 51% of hypertensive patients Singapore Med J 2009; 50(12) : 1180 Table IV. Association between severity of retinopathy and left ventricular hypertrophy on echocardiography. Severity of LVH on echocardiography Normal Retinal examination, no. (%) of patients Grade 1 Grade 2 Grade 3 Grade 4 Total Mild Moderate Severe Total 36 (61.0) 14 (38.9) 7 (100.) 57 (55.9) 59 36 7 102 6 (10.2) 2 (5.6) 0 (0.0) 8 (7.8) 13 (22.0) 16 (44.4) 0 (0.0) 29 (28.4) 1 (1.7) 3 (8.3) 0 (0.0) 4 (3.9) 3 (5.1) 1 (2.8) 0 (0.0) 4 (3.9) LVH: left ventricular hypertrophy patients who suffer from LVH.(17) In Dahlöf et al’s study, a positive correlation between the vascular involvement of the retina in the untreated hypertensive patients and left ventricular wall thickness on echocardiography was reported.(48) This study was in contrast with the results of our study, which showed no significant relationship between LVH and retinopathy, although it did indicate that the retinopathy severity increases with increasing LVH grading. This difference between the two studies could be due to the study criteria of retinopathy used by Dahlöf et al, which were not based on the standard Table V. Blood urea nitrogen and serum creatinine in left ventricular hypertrophy on echocardiography of hypertensive patients. LVH on No. of echocardiography patients Mean ± SD BUN (mg/dL) Mean ± SD Cr (mg/dL) Mild Moderate Severe Total 18.7 ± 7.2 21.8 ± 10.3 30.2 ± 25.9 20.6 ± 10.8 0.9 ± 0.2 1.2 ± 1.6 1.8 ± 2.1 1.1 ± 1.1 59 36 7 102 BUN: blood urea nitrogen; Cr: serum creatinine; SD: standard deviation modified Keith-Wagener classification system, and their conclusion was based only on the presence or absence of the existing LV concentric remodelling did not affect the any retinal abnormality regardless of its severity.(48) occurrence of TODs.(49) Our results were similar to those In Cuspidi et al’s study in 2001 on 800 hypertensive in this study. Although increasing the LVH grading led to patients, the prevalence of Grades 1 and 2 retinopathy increasing the severity of retinopathy and proteinuria, the among hypertensive patients was 46% and 32%, association between LVH severity and these two forms respectively, and only a few patients (< 2%) showed of TOD was statistically not significant. The authors Grades 3 and 4 abnormalities. In our study, the also asserted that 14.9% of their HTN patients showed prevalence of Grades 1 and 2 retinopathy was 55.9% and a normal retinal pattern, while arteriolar narrowing 28.4%, respectively, which approximately correlated and arteriovenous crossing were respectively observed with Cuspidi et al’s report. However, in our study, the in 42.4% and 42.7% of patients.(50) In another study by frequency of patients who had Grades 3 and 4 retinopathy the same group, two independent ophthalmologists was less than those with Grades 1 and 2, but it was still examined the same group of hypertensive patients with more than that in Cuspidi et al’s study. This difference the following results: Examiner 1: normal 15.2%; Group could be due to our LVH patient population which had I 25.4%; Group II 58.9%; Group III 0.5%; and Examiner more severe and prolonged HTN compared to Cuspidi 2: normal 14.7%; Group I 27.9%; Group II 56.8%; Group et al’s study population, and it is therefore logical to III 0.5%.(3) The results of this study was approximately expect higher grades of retinopathic disorder to be more similar to their previous research conducted in 2001. prevalent among our study population. In contrast, the prevalence of normal retina in our (16) In 2002, Cuspidi et al again investigated the investigated population (7.8%) was less than that in relationship between TOD and LV concentric remodelling. the previous study, but the prevalence of Grade 1 and 2 Two groups of never-treated essential hypertensive retinopathies was relatively similar. This difference was patients, 31 with normal LV geometry (Group I, again due to the difference in study criteria between the relative wall thickness 0.39) and 31 with LV concentric patient populations. remodelling (Group II, relative wall thickness 0.47), were included in the study. These groups were matched for examined the relationship between retinal arteriolar age, gender, body mass index and mean 24-hour systolic narrowing and LVH in patients with HTN. The BP. No significant difference was found between the researchers found no significant correlation between two groups regarding the prevalence of retinal changes the arteriole-to-venule ratios and LVM. However, they and microalbuminuria. The authors suggested that in suggested that further clinical studies were required to hypertensive patients with similar BP and LVMI levels, clarify the correlation between early microvascular In accordance with our findings, Grosso et al also Singapore Med J 2009; 50(12) : 1181 changes and other clinical indicators of hypertensive organ damage.(1) Recently, Cuspidi et al described the between urinary albumin excretion and cardiovascular Viazzi et al in 2005 showed that the relationship prevalence of advanced retinal microvascular lesions. risk was well below the threshold of 2.5 mg/mmol in They also determined the associations of retinal women and 3.5 mg/mmol in men. Thus, using a value of microvascular lesions with cardiac and extracardiac 1.8 mg/mmol of albumin to creatinine ratio, they were signs of TOD in a large selected hypertensive population. able to identify a significantly greater percentage of TOD In a multivariate logistic regression analysis, although in patients with HTN. They asserted that albuminuria advanced retinopathy was significantly associated measurement was a suitable first step work-up in patients with LVH (odds ratio 4.0), no correlation was detected with HTN as well as a very cost-effective screening between retinopathy and microalbuminuria. They test.(53) In our study, although the protein excretion did concluded that retinal microvascular lesions and cardiac not correlate with the severity of LVH (as TOD), the and macrovascular markers of TOD were strongly related increase in serum creatinine was compatible with the to each other.(3) Our study confirmed the results of this LVH grading. investigation. Torun et al aimed to determine the frequency of exists between BP and LVH. Therefore, a tight control TOD in never-treated, mild-to-moderate HTN. They also of systolic and diastolic BPs in the first step of essential evaluated the beneficial properties of ABPM for detecting HTN can assist to postpone LVH. Secondly, the classic patients who were at high risk for TOD and cardiovascular ECG criteria for the detection of LVH is not a reliable disease in these groups. In this study, the frequency of the method for screening hypertensive patients for LVH, combination of TOD signs (microalbuminuria, LVH and particularly in mild to moderate degrees of the disease, hypertensive retinopathy) was higher in patients with HTN due to its low sensitivity. Lastly, there is no significant than in normal subjects (71.4% vs. 30%). They suggested correlation between retinopathy and LVH among essential that ABPM may provide useful clinical information to hypertensive patients. However, the serum levels of BUN detect patients who are at high risk for cardiovascular and creatinine show a significant association with LVH. Hence, we conclude that firstly, a strong relationship diseases and TOD in newly-diagnosed, mild-tomoderate HTN.(15) In our study, although proteinuria and AcknowledgEment retinopathy were not correlated exactly with the severity This study was carried out with the sponsorship of of HTN, the LVM and creatinine levels were significantly Golestan University of Medical Sciences, Iran. and positively associated with systolic and diastolic BPs. Ayodele et al confirmed these results in the same year and showed a positive association between systolic BP and TOD. They suggested that an early detection of patients with HTN and strict BP control should help in reducing TOD and other clinical complications in hypertensive patients.(2) Leoncini et al investigated the relationship between creatinine clearance and subclinical organ damages in 957 patients who were afflicted with primary HTN and had never been previously treated. They found that the risk of acquiring LVH or retinal vascular changes increased significantly with each SD decrease in creatinine clearance, regardless of the traditional cardiovascular risk factors. They suggested that the routine evaluation of creatinine clearance might be helpful for identifying HTN patients with a higher cardiovascular risk.(51) This corroborated with our current study, where there was a significant relationship between LVH grading and elevation creatinine. 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